Cancer is one of the leading causes of morbidity and mortality worldwide. Most types of cancer do not have a cure. Cancer immunotherapy, such as T cell-based immune checkpoint blockade immunotherapy, has recently emerged as an effective treatment that can result in durable efficacy in many types of human cancer. However, not all patients and types of cancer respond to immunotherapy. For instance, human colorectal cancer, except for microsatellite instability (MSI) colorectal cancer which accounts for less than 4% of human colon cancer, and pancreatic cancer do not respond to anti-PD-L1/PD-1 mAb immunotherapy.
While developing cancer therapies, researchers have focused on covalent modifications of DNA and histones, the two core components of eukaryotic chromatin, as the two major mechanisms of epigenetic regulation of gene expression. The methylation of lysine residues in histones, particularly in the N-terminal tails of histones H3 and H4 of the chromatin, play a fundamental role in the regulation of gene expression through modulating chromatin structure. Histone methyltransferase (“HMTase”) catalyzes the methylation of histones to modify chromatin structure, thereby influencing gene expression patterns during cellular processes. Recent studies have established a fundamental role of HMTase activity in developing treatment for human diseases, particularly human cancers. Unlike genetic mutations of oncogenes and tumor suppressor genes, which are permanent alterations in the cancer genome, histone methylation is a reversible process, which has made HMTases attractive molecular targets for cancer therapy.
DNA methylation and histone acetylation have been extensively studied and efforts have been devoted to develop DNA methylation inhibitors (for example, Decitabine) and histone acetylase inhibitors (for example, SAHA). Due to the complex nature of their mechanism of action, HMTases are often an ignored area and development of HMTase inhibitors are still in its infancy. For instance, chaetocin and verticillin A are the only two SUV39H1 inhibitors. SUV39H1 is an HMTase that catalyzes H3K9 trimethylation (“H3K9me3”), which is a hallmark of a transcriptionally repressive chromatin structure. H3K9me3 is well-known to be a silencer of tumor suppressors. However, both chaetocin and verticillin A have multiple targets and are toxic in vivo.
Therefore, it is an object of the invention to provide small molecule HMTase inhibitors and methods of their use.
It is another object of the invention to provide compositions and methods for treating hyperproliferative conditions or a symptom thereof.
It is another object of the invention to provide compositions and methods for killing cancer cells in a subject in need thereof.